Substantiallymonodispersed mixtures of polymers having polyethylene glycol moieties

ABSTRACT

Methods of synthesizing a substantially monodispersed mixture of polymers comprising polyethylene glycol moieties include: reacting a substantially monodispersed mixture of compounds having the structure of Formula I: 
 
R 1 (OC 2 H 4 ) b —O − X +   (I) 
         wherein R 1  is H or a lipophilic moiety; n is from 1 to 25; and X +  is a positive ion, with a substantially monodispersed mixture of compounds having the structure of Formula II: 
 
R 2 (OC 2 H 4 ) m —OMs   (II) 
   wherein R 2  is H or a lipophilic moiety; and m is from 1 to 25, under conditions sufficient to provide a substantially monodispersed mixture of polymers comprising polyethylene glycol moieties and having the structure of Formula III: 
 
R 2 (OC 2 H 4 ) m+n —OR 1    (III). 
Substantially monodispersed mixtures of polymers comprising polyethylene glycol moieties are also disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.09/873,731, filed Jun. 4, 2001, the disclosure of which is incorporatedby reference herein in its entirety.

FIELD OF THE INVENTION

The present invention relates to methods of synthesizing polymericcompounds, and more particularly, to methods of synthesizing polymericcompounds comprising polyethylene glycol moieties.

BACKGROUND OF THE INVENTION

Polyethylene glycol (PEG) is used in a wide variety of applicationsincluding, but not limited to, plasticizers, softeners, humectants,ointments, polishes, paper coating, mold lubricants, bases for cosmeticsand pharmaceuticals, solvents, binders, metal and rubber processing, andadditives to foods and animal feed. Some particular uses of PEG inpharmaceutical applications include, for example, formation of PEG-drugconjugates, treatment of neonatal respiratory distress syndrome,treatment of functional and/or chronic constipation, treatment ofencopresis in children, and diagnosis and therapy of gastrointestinaldiseases.

PEG is typically produced by base-catalyzed ring-opening polymerizationof ethylene oxide. The reaction is initiated by adding ethylene oxide toethylene glycol, with potassium hydroxide as catalyst. This processresults in a polydispersed mixture of polyethylene glycol polymershaving a molecular weight within a given range of molecular weights. Forexample, PEG products offered by Sigma-Aldrich of Milwaukee, Wis. areprovided in polydispersed mixtures such as PEG 400 (M_(n) 380-420); PEG1,000 (M_(n) 950-1,050); PEG 1,500 (M_(n) 1,400-1,600); and PEG 2,000(M_(n) 1,900-2,200).

In J. Milton Harris, Laboratory Synthesis of Polyethylene GlycolDerivatives, 25(3) Rev. Macromol. Chem. Phys. 325-373 (1985), the authordiscusses synthesis of monomethyl ethers of PEG (also known asmethyl-terminated PEG or mPEG). The reference states that mPEG containsa significant amount (as much as 25%; from size exclusionchromatography) of PEG without the methoxy end group. This PEG“impurity” may result from water present in the polymerization process.Under basic conditions, hydroxide is produced, which yields PEG uponreaction with the ethylene oxide monomer. Since the hydroxide-initiatedPEG chain can grow at both ends, while the methoxide-initiated chain cangrow from only one end, the resulting mixture has a broader molecularweight distribution than that for the PEG's.

While these polydispersed mixtures of PEGs and/or mPEGs may be usefulfor some applications, physical properties of polymers may vary with thelength of the polymer. Thus, polydispersed mixtures may not be suitablefor certain applications that require specific physical properties.Additionally, the heterogeneity of commercially available PEGs and mPEGsmay complicate spectroscopic analysis, physico-chemical characterizationand pharmacokinetics analysis. As a result, it is desirable to providemonodispersed mixtures of PEGs and/or mPEGs.

Monodispersed mixtures of PEG and/or mPEG polymers may be provided byvarious organic synthesis routes. For example, in Yiyan Chen & GregoryL. Baker, Synthesis and Properties of ABA Amphiphiles, 64 J. Org. Chem.6870-6873 (1999), the authors propose the following scheme:

This synthesis route may be inconvenient due to the number of stepsrequired as well as the use of undesirable reaction conditions such ashigh temperatures that may actually break down the PEG polymer.Moreover, it may be difficult to purify the product as the startingmaterial may always be present in the reaction mixture.

In Gérard Coudert et al., A Novel, Unequivocal Synthesis of PolyethyleneGlycols, Synthetic Communications, 16(1): 19-26 (1986), the authorsproposed the following synthesis route:

This synthesis route may be inconvenient due to the undesirable reactionconditions, which do not lead to mPEG.

As a result, it is desirable to provide a new route for synthesizingPEG, mPEG, and/or polymers comprising a PEG moiety that are moreefficient and do not require such undesirable reaction conditions.

SUMMARY OF THE INVENTION

Embodiments of the present invention provide improved methods forsynthesizing substantially monodispersed mixtures of polymers comprisingpolyethylene glycol moieties. Methods according to embodiments of thepresent invention may utilize reaction conditions that are milder thanthose required by the conventional methods described above. For example,many, if not all, of the steps of methods according to embodiments ofthe present invention may be carried out at atmospheric pressure and/orat room temperature. The ability to perform these steps at atmosphericpressure and/or temperature may reduce or prevent the formation ofundesirable side products. Additionally, methods according toembodiments of the present invention may be more efficient than theconventional methods described above. For example, methods according toembodiments of the present invention may require fewer steps and/or lesstime than the conventional methods described above. Methods according toembodiments of the present invention may provide the ability to removePEG starting materials from the products comprising polyethylene glycolmoieties to provide substantially monodispersed mixtures of polymerscomprising polyethylene glycol moieties.

According to embodiments of the present invention, a method ofsynthesizing a substantially monodispersed mixture of polymerscomprising polyethylene glycol moieties includes:

-   -   reacting a substantially monodispersed mixture of compounds        having the structure of Formula I:        R¹(OC₂H₄)_(n)—O⁻X⁺  (I)    -   wherein R¹ is H or a lipophilic moiety; n is from 1 to 25; and        X⁺ is a positive ion,        with a substantially monodispersed mixture of compounds having        the structure of Formula II:        R²(OC₂H₄)_(m)—OMs   (II)    -   wherein R² is H or a lipophilic moiety; and m is from 1 to 25,        under conditions sufficient to provide a substantially        monodispersed mixture of polymers comprising polyethylene glycol        moieties and having the structure of Formula III:        R²(OC₂H₄)_(m+n)—OR¹   (III).

Methods according to embodiments of the present invention may providemore efficient synthesis routes for substantially monodispersed mixturesof PEGs, substantially monodispersed mixtures of mPEGs and/orsubstantially monodispersed mixtures of polymers comprising PEGmoieties. Methods of the present invention may reduce the number ofsteps and/or reduce the overall synthesis time compared to conventionalmethods of synthesizing PEG polymers. Methods of the present inventionmay also utilize milder reaction conditions than those used inconventional methods.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a generic scheme for synthesizing a mixture ofactivated polymers comprising a polyethylene glycol moiety and a fattyacid moiety according to embodiments of the present invention;

FIG. 2 illustrates a scheme for synthesizing a mixture of activatedmPEG7-hexyl oligomers according to embodiments of the present invention;and

FIG. 3 illustrates a scheme for synthesizing a mixture of mPEG accordingto embodiments of the present invention.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The invention will now be described with respect to preferredembodiments described herein. It should be appreciated however thatthese embodiments are for the purpose of illustrating the invention, andare not to be construed as limiting the scope of the invention asdefined by the claims.

As used herein, the term “non-polydispersed” is used to describe amixture of compounds having a dispersity that is in contrast to thepolydispersed mixtures of PEG products offered by Sigma-Aldrich ofMilwaukee, Wis. such as PEG 400 (M_(n) 380-420); PEG 1,000 (M_(n)950-1,050); PEG 1,500 (M_(n) 1,400-1,600); and PEG 2,000 (M_(n)1,900-2,200).

As used herein, the term “substantially monodispersed” is used todescribe a mixture of compounds wherein at least about 95 percent of thecompounds in the mixture have the same molecular weight.

As used herein, the term “monodispersed” is used to describe a mixtureof compounds wherein about 100 percent of the compounds in the mixturehave the same molecular weight.

As used herein, the term “weight average molecular weight” is defined asthe sum of the products of the weight fraction for a given molecule inthe mixture times the mass of the molecule for each molecule in themixture. The “weight average molecular weight” is represented by thesymbol M_(w).

As used herein, the term “number average molecular weight” is defined asthe total weight of a mixture divided by the number of molecules in themixture and is represented by the symbol M_(n).

As used herein, the term “PEG” refers to straight or branchedpolyethylene glycol polymers, and includes the monomethylether ofpolyethylene glycol (mPEG). The terms “PEG subunit” and polyethyleneglycol subunit refer to a single polyethylene glycol unit, i.e.,—(CH₂CH₂O)—.

As used herein, the term “lipophilic” means the ability to dissolve inlipids and/or the ability to penetrate, interact with and/or traversebiological membranes, and the term, “lipophilic moiety” or “lipophile”means a moiety which is lipophilic and/or which, when attached toanother chemical entity, increases the lipophilicity of such chemicalentity. Examples of lipophilic moieties include, but are not limited to,alkyls, fatty acids, esters of fatty acids, cholesteryl, adamantyl andthe like.

As used herein, the term “lower alkyl” refers to substituted orunsubstituted alkyl moieties having from 1 to 5 carbon atoms.

As used herein, the term “higher alkyl” refers to substituted orunsubstituted alkyl moieties having 6 or more carbon atoms.

According to aspects of the present invention, a substantiallymonodispersed mixture of polymers comprising polyethylene glycolmoieties is provided as illustrated in reaction 1:

R¹ is H or a lipophilic moiety. R¹ is preferably H, alkyl, aryl alkyl,an aromatic moiety, a fatty acid moiety, an ester of a fatty acidmoiety, cholesteryl, or adamantyl. R¹ is more preferably H, lower alkyl,or an aromatic moiety. R¹ is most preferably H, methyl, or benzyl.

The value of n is from 1 to 25. Preferably n is from 1 to 6.

X⁺ is a positive ion. Preferably X⁺ is any positive ion in a compound,such as a strong base, that is capable of ionizing a hydroxyl moiety onPEG. Examples of positive ions include, but are not limited to, sodiumions, potassium ions, lithium ions, cesium ions, and thallium ions.

R² is H or a lipophilic moiety. R² is preferably branched or linearalkyl, aryl alkyl, an aromatic moiety, a fatty acid moiety, or an esterof a fatty acid moiety. R² is more preferably lower alkyl, benzyl, afatty acid moiety having 1 to 24 carbon atoms, or an ester of a fattyacid moiety having 1 to 24 carbon atoms. R² is most preferably methyl, afatty acid moiety having 1 to 18 carbon atoms or an ethyl ester of afatty acid moiety having 1 to 18 carbon atoms.

The value of m is from 1 to 25. Preferably m is from 1 to 6.

Ms is a mesylate moiety (i.e., CH₃S(O₂)—).

As illustrated in reaction 1, a mixture of compounds having thestructure of Formula I is reacted with a mixture of compounds having thestructure of Formula II to provide a mixture of polymers comprisingpolyethylene glycol moieties and having the structure of Formula III.The mixture of compounds having the structure of Formula I is asubstantially monodispersed mixture. Preferably, at least 96, 97, 98 or99 percent of the compounds in the mixture of compounds of Formula Ihave the same molecular weight, and, more preferably, the mixture ofcompounds of Formula I is a monodispersed mixture. The mixture ofcompounds of Formula II is a substantially monodispersed mixture.Preferably, at least 96, 97, 98 or 99 percent of the compounds in themixture of compounds of Formula II have the same molecular weight, and,more preferably, the mixture of compounds of Formula II is amonodispersed mixture. The mixture of compounds of Formula III is asubstantially monodispersed mixture. Preferably, at least 96, 97, 98 or99 percent of the compounds in the mixture of compound of Formula IIIhave the same molecular weight. More preferably, the mixture ofcompounds of Formula III is a monodispersed mixture.

Reaction 1 is preferably performed between about 0° C. and about 40° C.,is more preferably performed between about 15° C. and about 35° C., andis most preferably performed at room temperature (approximately 25° C.).

Reaction 1 may be performed for various periods of time as will beunderstood by those skilled in the art. Reaction 1 is preferablyperformed for a period of time between about 0.25, 0.5 or 0.75 hours andabout 2, 4 or 8 hours.

Reaction 1 is preferably carried out in an aprotic solvent such as, butnot limited to, N,N-dimethylacetamide (DMA), N,N-dimethylformamide(DMF), dimethyl sulfoxide, hexamethylphosphoric triamide,tetrahydrofuran (THF), dioxane, diethyl ether, methyl t-butyl ether(MTBE), toluene, benzene, hexane, pentane, N-methylpyrollidinone,tetrahydronaphthalene, decahydronaphthalene, 1,2-dichlorobenzene,1,3-dimethyl-2-imidazolidinone, or a mixture thereof. More preferably,the solvent is DMF, DMA or toluene.

The molar ratio of the compound of Formula I to the compound of FormulaII is preferably greater than about 1:1. More preferably, the molarratio is at least about 2:1. By providing an excess of the compounds ofFormula I, one can ensure that substantially all of the compounds ofFormula II are reacted, which may aid in the recovery of the compoundsof Formula III as discussed below.

Compounds of Formula I are preferably prepared as illustrated inreaction 2:

R¹ and X⁺ are as described above and the mixture of compounds of FormulaIV is substantially monodispersed; preferably, at least 96, 97, 98 or 99percent of the compounds in the mixture of compounds of Formula IV havethe same molecular weight; and, more preferably, the mixture ofcompounds of Formula IV is a monodispersed mixture.

Various compounds capable of ionizing a hydroxyl moiety on the PEGmoiety of the compound of Formula IV will be understood by those skilledin the art. The compound capable of ionizing a hydroxyl moiety ispreferably a strong base. More preferably, the compound capable ofionizing a hydroxyl moiety is selected from the group consisting ofsodium hydride, potassium hydride, sodium t-butoxide, potassiumt-butoxide, butyl lithium (BuLi), and lithium disopropylamine. Thecompound capable of ionizing a hydroxyl moiety is more preferably sodiumhydride.

The molar ratio of the compound capable of ionizing a hydroxyl moiety onthe PEG moiety of the compound of Formula IV to the compound of FormulaIV is preferably at least about 1: 1, and is more preferably at leastabout 2:1. By providing an excess of the compound capable of ionizingthe hydroxyl moiety, it is assured that substantially all of thecompounds of Formula IV are reacted to provide the compounds of FormulaI. Thus, separation difficulties, which may occur if both compounds ofFormula IV and compounds of Formula I were present in the reactionproduct mixture, may be avoided.

Reaction 2 is preferably performed between about 0° C. and about 40° C.,is more preferably performed between about 0° C. and about 35° C., andis most preferably performed between about 0° C. and room temperature(approximately 25° C.).

Reaction 2 may be performed for various periods of time as will beunderstood by those skilled in the art. Reaction 2 is preferablyperformed for a period of time between about 0.25, 0.5 or 0.75 hours andabout 2, 4 or 8 hours.

Reaction 2 is preferably carried out in an aprotic solvent such as, butnot limited to, N,N-dimethylacetamide (DMA), N,N-dimethylformamide(DMF), dimethyl sulfoxide, hexamethylphosphoric triamide,tetrahydrofuran (THF), dioxane, diethyl ether, methyl t-butyl ether(MTBE), toluene, benzene, hexane, pentane, N-methylpyrollidinone,dichloromethane, chloroform, tetrahydronaphthalene,decahydronaphthalene, 1,2-dichlorobenzene,1,3-dimethyl-2-imidazolidinone, or a mixture thereof. More preferably,the solvent is DMF, dichloromethane or toluene.

Compounds of Formula II are preferably prepared as illustrated inreaction 3:

R² and Ms are as described above and the compound of Formula V ispresent as a substantially monodispersed mixture of compounds of FormulaV; preferably at least 96, 97, 98 or 99 percent of the compounds in themixture of compounds of Formula V have the same molecular weight; and,more preferably, the mixture of compounds of Formula V is amonodispersed mixture.

Q is a halide, preferably chloride or fluoride.

CH₃S(O₂)Q is methanesulfonyl halide. The methanesulfonyl halide ispreferably methanesulfonyl chloride or methanesulfonyl fluoride. Morepreferably, the methanesulfonyl halide is methanesulfonyl chloride.

The molar ratio of the methane sulfonyl halide to the compound ofFormula V is preferably greater than about 1:1, and is more preferablyat least about 2:1. By providing an excess of the methane sulfonylhalide, it is assured that substantially all of the compounds of FormulaV are reacted to provide the compounds of Formula II. Thus, separationdifficulties, which may occur if both compounds of Formula V andcompounds of Formula II were present in the reaction product mixture,may be avoided.

Reaction 3 is preferably performed between about −10° C. and about 40°C., is more preferably performed between about 0° C. and about 35° C.,and is most preferably performed between about 0° C. and roomtemperature (approximately 25° C.).

Reaction 3 may be performed for various periods of time as will beunderstood by those skilled in the art. Reaction 3 is preferablyperformed for a period of time between about 0.25, 0.5 or 0.75 hours andabout 2, 4 or 8 hours.

Reaction 3 is preferably carried out in the presence of an aliphaticamine including, but not limited to, monomethylamine, dimethylamine,trimethylamine, monoethylamine, diethylamine, triethylamine,monoisopropylamine, diisopropylamine, mono-n-butylamine,di-n-butylamine, tri-n-butylamine, monocyclohexylamine,dicyclohexylamine, or mixtures thereof. More preferably, the aliphaticamine is a tertiary amine such as triethylamine.

As will be understood by those skilled in the art, various substantiallymonodispersed mixtures of compounds of Formula V are commerciallyavailable. For example, when R² is H or methyl, the compounds of FormulaV are PEG or mPEG compounds, respectively, which are commerciallyavailable from Aldrich of Milwaukee, Wis.; Fluka of Switzerland, and/orTCl America of Portland, Oreg.

When R² is a lipophilic moiety such as, for example, higher alkyl, fattyacid, an ester of a fatty acid, cholesteryl, or adamantyl, the compoundsof Formula V may be provided by various methods as will be understood bythose skilled in the art. The compounds of Formula V are preferablyprovided as follows:

R² is a lipophilic moiety, preferably higher alkyl, fatty acid ester,cholesteryl, or adamantyl, more preferably a lower alkyl ester of afatty acid, and most preferably an ethyl ester of a fatty acid havingfrom 1 to 18 carbon atoms.

R³ is H, benzyl, trityl, tetrahydropyran, or other alcohol protectinggroups as will be understood by those skilled in the art.

X₂ ⁺ is a positive ion as described above with respect to X⁺.

The value of m is as described above.

Regarding reaction 4, a mixture of compounds of Formula VI is reactedwith a mixture of compounds of Formula VII under reaction conditionssimilar to those described above with reference to reaction 1. Themixture of compounds of Formula VI is a substantially monodispersedmixture. Preferably, at least 96, 97, 98 or 99 percent of the compoundsin the mixture of compounds of Formula VI have the same molecularweight. More preferably, the mixture of compounds of Formula VI is amonodispersed mixture. The mixture of compounds of Formula VII is asubstantially monodispersed mixture. Preferably, at least 96, 97, 98 or99 percent of the compounds in the mixture of compounds of Formula VIIhave the same molecular weight. More preferably, the mixture ofcompounds of Formula VII is a monodispersed mixture.

Regarding reaction 5, the compound of Formula VIII may be hydrolyzed toconvert the R³ moiety into an alcohol by various methods as will beunderstood by those skilled in the art. When R³ is benzyl or trityl, thehydrolysis is preferably performed utilizing H₂ in the presence of apalladium-charcoal catalyst as is known by those skilled in the art. Ofcourse, when R³ is H, reaction 5 is unnecessary.

The compound of Formula VI may be commercially available or be providedas described above with reference to reaction 3. The compound of FormulaVII may be provided as described above with reference to reaction 2.

Substantially monodispersed mixtures of polymers comprising PEG moietiesand having the structure of Formula III above can further be reactedwith other substantially monodispersed polymers comprising PEG moietiesin order to extend the PEG chain. For example, the following scheme maybe employed:

Ms, m and n are as described above with reference to reaction 1; p issimilar to n and m, and X₂ ⁺ is similar to X⁺ as described above withreference to reaction 1. Q is as described above with reference toreaction 3. R² is as described above with reference to reaction 1 and ispreferably lower alkyl. R¹ is H. Reaction 6 is preferably performed in amanner similar to that described above with reference to reaction 3.Reaction 7 is preferably performed in a manner similar to that describedabove with reference to reaction 1. Preferably, at least 96, 97, 98 or99 percent of the compounds in the mixture of compounds of Formula IIIhave the same molecular weight, and, more preferably, the mixture ofcompounds of Formula III is a monodispersed mixture. The mixture ofcompounds of Formula X is a substantially monodispersed mixture.Preferably, at least 96, 97, 98 or 99 percent of the compounds in themixture of compounds of Formula X have the same molecular weight, and,more preferably, the mixture of compounds of Formula X is amonodispersed mixture.

An embodiment of a method according to the present invention isillustrated by the scheme shown in FIG. 1, which will now be described.The synthesis of a substantially monodispersed mixture of polyethyleneglycol-containing oligomers begins by the preparation of the monobenzylether (XII) of a substantially monodispersed mixture of polyethyleneglycol. An excess of a commercially available substantiallymonodispersed mixture of polyethylene glycol is reacted with benzylchloride in the presence of aqueous sodium hydroxide as described byCoudert et al (Synthetic Communications, 16(1): 19-26 (1986)). Thesodium salt of XII is then prepared by the addition of NaH, and thissodium salt is allowed to react with the mesylate synthesized from theester of a hydroxyalkanoic acid (XIII). The product (XIV) of thedisplacement of the mesylate is debenzylated via catalytic hydrogenationto obtain the alcohol (XV). The mesylate (XVI) of this alcohol may beprepared by addition of methanesulfonyl chloride and used as theelectrophile in the reaction with the sodium salt of the monomethylether of a substantially monodispersed mixture of a polyethylene glycolderivative, thereby extending the polyethylene glycol portion of theoligomer to the desired length, obtaining the elongated ester (XVII).The ester may be hydrolyzed to the acid (XVIII) in aqueous base andtransformed into the activated ester (XIX) by reaction with acarbodiimide and N-hydroxysuccinimide. While the oligomer illustrated inFIG. 1 is activated using N-hydroxysuccinimide, it is to be understoodthat various other reagents may be used to activate oligomers of thepresent invention including, but not limited to, active phenylchloroformates such as para-nitrophenyl chloroformate, phenylchloroformate, 3,4-phenyldichloroformate, and 3,4-phenyldichloroformate;tresylation; and acetal formation.

Still referring to FIG. 1, q is from 1 to 24. Preferably, q is from 1 to18, and q is more preferably from 4 to 16. R⁴ is a moiety capable ofundergoing hydrolysis to provide the carboxylic acid. R⁴ is preferablylower alkyl and is more preferably ethyl. The variables n and m are asdescribed above with reference to reaction 1.

All starting materials used in the procedures described herein areeither commercially available or can be prepared by methods known in theart using commercially available starting materials.

The present invention will now be described with reference to thefollowing examples. It should be appreciated that these examples are forthe purposes of illustrating aspects of the present invention, and donot limit the scope of the invention as defined by the claims.

EXAMPLES

Examples 1 through 6 refer to the scheme illustrated in FIG. 2.

Example 1 Hexaethylene glycol monobenzyl ether (XX)

An aqueous sodium hydroxide solution prepared by dissolving 3.99 g (100mmol) NaOH in 4 ml water was added slowly to non-polydispersedhexaethylene glycol (28.175 g, 25 ml, 100 mmol). Benzyl chloride (3.9 g,30.8 mmol, 3.54 ml) was added and the reaction mixture was heated withstirring to 100° C. for 18 hours. The reaction mixture was then cooled,diluted with brine (250 ml) and extracted with methylene chloride (200ml×2). The combined organic layers were washed with brine once, driedover Na₂SO₄, filtered and concentrated in vacuo to a dark brown oil. Thecrude product mixture was purified via flash chromatography (silica gel,gradient elution: ethyl acetate to 9/1 ethyl acetate/methanol) to yield8.099 g (70%) of non-polydispersed XX as a yellow oil.

Example 2 Ethyl 6-methylsulfonyloxyhexanoate (XXI)

A solution of non-polydispersed ethyl 6-hydroxyhexanoate (50.76 ml,50.41 g, 227 mmol) in dry dichloromethane (75 ml) was chilled in a icebath and placed under a nitrogen atmosphere. Triethylamine (34.43 ml,24.99 g, 247 mmol) was added. A solution of methanesulfonyl chloride(19.15 ml, 28.3 g, 247 mmol) in dry dichloromethane (75 ml) was addeddropwise from an addition funnel. The mixture was stirred for three andone half hours, slowly being allowed to come to room temperature as theice bath melted. The mixture was filtered through silica gel, and thefiltrate was washed successively with water, saturated NaHCO₃, water andbrine. The organics were dried over Na₂SO₄, filtered and concentrated invacuo to a pale yellow oil. Final purification of the crude product wasachieved by flash chromatography (silica gel, 1/1 hexanes/ethyl acetate)to give the non-polydispersed product (46.13 g, 85 %) as a clear,colorless oil. FAB MS: m/e 239 (M+H), 193 (M-C₂H₅O).

Example 36-{2-[2-(2-{2-[2-(2-Benzyloxyethoxy)ethoxy]ethoxy}-ethoxy)-ethoxy]-ethoxy}-hexanoicacid ethyl ester (XXII)

Sodium hydride (3.225 g or a 60% oil dispersion, 80.6 mmol) wassuspended in 80 ml of anhydrous toluene, placed under a nitrogenatmosphere and cooled in an ice bath. A solution of thenon-polydispersed alcohol XX (27.3 g, 73.3 mmol) in 80 ml dry toluenewas added to the NaH suspension. The mixture was stirred at 0° C. forthirty minutes, allowed to come to room temperature and stirred foranother five hours, during which time the mixture became a clear brownsolution. The non-polydispersed mesylate XXI (19.21 g, 80.6 mmol) in 80ml dry toluene was added to the NaH/alcohol mixture, and the combinedsolutions were stirred at room temperature for three days. The reactionmixture was quenched with 50 ml methanol and filtered through basicalumina. The filtrate was concentrated in vacuo and purified by flashchromatography (silica gel, gradient elution: 3/1 ethyl acetate/hexanesto ethyl acetate) to yield the non-polydispersed product as a paleyellow oil (16.52 g, 44%). FAB MS: m/e 515 (M+H).

Example 36-{2-[2-(2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}-ethoxy)-ethoxy]-ethoxy}-hexanoicacid ethyl ester (XXIII)

Non-polydispersed benzyl ether XI (1.03 g, 2.0 mmol) was dissolved in 25ml ethanol. To this solution was added 270 mg 10% Pd/C, and the mixturewas placed under a hydrogen atmosphere and stirred for four hours, atwhich time TLC showed the complete disappearance of the startingmaterial. The reaction mixture was filtered through Celite 545 to removethe catalyst, and the filtrate was concentrated in vacuo to yield thenon-polydispersed title compound as a clear oil (0.67 g, 79%). FAB MS:m/e 425 (M+H), 447 (M+Na).

Example 46-{2-[2-(2-{2-[2-(2-methylsulfonylethoxy)ethoxy]ethoxy}-ethoxy)-ethoxy]-ethoxy}-hexanoicacid ethyl ester (XXIV)

The non-polydispersed alcohol XXIII (0.835 g, 1.97 mmol) was dissolvedin 3.5 ml dry dichloromethane and placed under a nitrogen atmosphere.Triethylamine (0.301 ml, 0.219 g, 2.16 mmol) was added and the mixturewas chilled in an ice bath. After two minutes, the methanesulfonylchloride (0.16 ml; 0.248 g, 2.16 mmol) was added. The mixture wasstirred for 15 minutes at 0° C., then at room temperature for two hours.The reaction mixture was filtered through silica gel to remove thetriethylammonium chloride, and the filtrate was washed successively withwater, saturated NaHCO₃, water and brine. The organics were dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography (silica gel, 9/1 ethyl acetate/methanol) to givenon-polydispersed XXIV as a clear oil (0.819 g, 83%). FAB MS: m/e 503(M+H).

Example 58-[2-(2-{2-[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-hexanoicacid ethyl ester (XXV)

NaH (88 mg of a 60% dispersion in oil, 2.2 mmol) was suspended inanhydrous toluene (3 ml) under N₂ and chilled to 0° C. Non-polydisperseddiethylene glycol monomethyl ether (0.26 ml, 0.26 g, 2.2 mmol) that hadbeen dried via azeotropic distillation with toluene was added. Thereaction mixture was allowed to warm to room temperature and stirred forfour hours, during which time the cloudy grey suspension became clearand yellow and then turned brown. Non-polydispersed mesylate XXIV (0.50g, 1.0 mmol) in 2.5 ml dry toluene was added. After stirring at roomtemperature over night, the reaction was quenched by the addition of 2ml of methanol and the resultant solution was filtered through silicagel. The filtrate was concentrated in vacuo and the FAB MS: m/e 499(M+H), 521 (M+Na). Additional purification by preparatory chromatography(silica gel, 19/3 chloroform/methanol) provided the non-polydispersedproduct as a clear yellow oil (0.302 g 57%). FAB MS: m/e 527 (M+H), 549(M+Na).

Example 68-[2-(2-{2-[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-hexanoicacid (XXVI)

Non-polydispersed ester XXV (0.25 g, 0.46 mmol) was stirred for 18 hoursin 0.71 ml of 1 N NaOH. After 18 hours, the mixture was concentrated invacuo to remove the alcohol and the residue dissolved in a further 10 mlof water. The aqueous solution was acidified to pH 2 with 2 N HCl andthe product was extracted into dichloromethane (30 ml×2). The combinedorganics were then washed with brine (25 ml×2), dried over Na₂SO₄,filtered and concentrated in vacuo to yield the non-polydispersed titlecompound as a yellow oil (0.147 g, 62%). FAB MS: m/e 499 (M+H), 521(M+Na).

Example 78-[2-(2-{2-[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-hexanoicacid 2,5-dioxo-pyrrolidin-1-yl ester (XXVII)

Non-polydispersed acid XXVI (0.209 g, 0.42 mmol) were dissolved in 4 mlof dry dichloromethane and added to a dry flask already containing NHS(N-hydroxysuccinimide) (57.8 mg, 0.502 mmol) and EDC(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) (98.0 mg,0.502 mmol) under a N₂ atmosphere. The solution was stirred at roomtemperature overnight and filtered through silica gel to remove excessreagents and the urea formed from the EDC. The filtrate was concentratedin vacuo to provide the non-polydispersed product as a dark yellow oil(0.235 g, 94%). FAB MS: m/e 596 (M+H), 618 (M+Na).

Examples 8 through 17

Reactions in Examples 8 through 17 were carried out under nitrogen withmagnetic stirring, unless otherwise specified. “Work-up” denotesextraction with an organic solvent, washing of the organic phase withsaturated NaCl solution, drying (MgSO₄), and evaporation (rotaryevaporator). Thin layer chromatography was conducted with Merck glassplates precoated with silica gel 60° F.-254 and spots were visualized byiodine vapor. All mass spectra were determined by MacromolecularResources Colorado State University, Colo. and are reported in the orderm/z, (relative intensity). Elemental analyses and melting points wereperformed by Galbraith Laboratories, Inc., Knoxville, Tenn. Examples8-17 refer to the scheme illustrated in FIG. 3.

Example 8 8-Methoxy-1-(methylsulfonyl)oxy-3,6-dioxaoctane (XXXI)

A solution of non-polydispersed triethylene glycol monomethyl ethermolecules (4.00 mL, 4.19 g, 25.5 mmol) and triethylamine (4.26 mL, 3.09g, 30.6 mmol) in dry dichloromethane (50 mL) was chilled in an ice bathand place under a nitrogen atmosphere. A solution of methanesulfonylchloride (2.37 mL, 3.51 g, 30.6 mmol) in dry dichloromethane (20 mL) wasadded dropwise from an addition funnel. Ten minutes after the completionof the chloride addition, the reaction mixture was removed from the icebath and allowed to come to room temperature. The mixture was stirredfor an additional hour, at which time TLC (CHCl₃ with 15% MeOH as theelutant) showed no remaining triethylene glycol monomethyl ether.

The reaction mixture was diluted with another 75 mL of dichloromethaneand washed successively with saturated NaHCO₃, water and brine. Theorganics were dried over Na₂SO₄, filtered and concentrated in vacuo togive non-polydispersed compound XXXI as a clear oil (5.31 g, 86%).

Example 9 Ethylene glycol mono methyl ether (XXXII) (m=4,5,6)

To a stirred solution of non-polydispersed compound XXVIII (35.7 mmol)in dry DMF (25.7 mL), under N₂ was added in portion a 60% dispersion ofNaH in mineral oil, and the mixture was stirred at room temperature for1 hour. To this salt XXIX was added a solution of non-polydispersedmesylate XXXI (23.36) in dry DMF (4 ml) in a single portion, and themixture was stirred at room temperature for 3.5 hours. Progress of thereaction was monitored by TLC (12% CH₃OH—CHCl₃). The reaction mixturewas diluted with an equal amount of 1N HCl, and extracted with ethylacetate (2×20 ml) and discarded. Extraction of aqueous solution andwork-up gave non-polydispersed polymer XXXII (82-84% yield).

Example 10 3,6,9,12,15,18,21-Heptaoxadocosanol (XXXII) (m=4)

Oil; Rf 0.46 (methanol: chloroform=3:22); MS m/z calc'd for C₁₅H₃₂O₈340.21 (M⁺+1), found 341.2.

Example 11 3,6,9,12,15,18,21,24-Octaoxapentacosanol (XXXII) (m=5)

Oil; Rf 0.43 (methanol: chloroform=6:10); MS m/z calc'd for C₁₇H₃₆O₉384.24 (M⁺+1), found 385.3.

Example 12 3,6,9,12,15,18,21,24,27-Nonaoxaoctacosanol (XXXII) (m=5)

Oil; Rf 0.42 (methanol: chloroform=6:10); MS m/z calc'd for C₁₉H₄₀O₁₀428.26 (M⁺+1), found 429.3.

Example 1320-methoxy-1-(methylsulfonyl)oxy-3,6,9,12,15,18-hexaoxaeicosane (XXXIII)

Non-polydispersed compound XXXIII was obtained in quantitative yieldfrom the alcohol XXXII (m=4) and methanesulfonyl chloride as describedfor XXXI, as an oil; Rf 0.4 (ethyl acetate: acetonitrile=1:5); MS m/zcalc'd for C₁₇H₃₇O₁₀ 433.21 (M⁺+1), found 433.469.

Example 14 Ethylene glycol mono methyl ether (XXXIV) (m=3,4,5)

The non-polydispersed compounds XXXIV were prepared from a diol by usingthe procedure described above for compound XXXII.

Example 15 3,6,9,12,15,18,21,24,27,30-Decaoxaheneicosanol (XXXIV) (m=3)

Oil; Rf 0.41 (methanol: chloroform=6:10); MS m/z calc'd for C₂₁H₄₄O₁₁472.29 (M⁺+1), found 472.29.

Example 16 3,6,9,12,15,18,21,24,27,30,33-Unecaoxatetratricosanol (XXXIV)(m=4)

Oil; Rf 0.41 (methanol: chloroform=6:10); MS m/z calc'd for C₂₃H₄₈O₁₂516.31 (M⁺+1), found 516.31.

Example 17 3,6,9,12,15,18,21,24,27,30,33,36-Dodecaoxaheptatricosanol(XXXIV) (m=5)

Oil; Rf 0.41 (methanol: chloroform=6:10); MS m/z calc'd for C₂₅H₅₂O₁₃560.67 (M⁺+1), found 560.67.

In the specification, there has been disclosed typical preferredembodiments of the invention and, although specific terms are employed,they are used in a generic and descriptive sense only and not forpurposes of limitation, the scope of the invention being set forth inthe following claims.

1. A substantially monodispersed mixture of polymers, wherein at least95 percent of the polymers in the mixture each comprise a polyethyleneglycol moiety having from 7 to 50 polyethylene glycol subunits, andwherein the at least 95 percent of the polymers in the mixture each havethe same number of polyethylene glycol subunits.
 2. The mixture ofpolymers of claim 1, wherein at least 96 percent of the polymers in themixture have the same molecular weight, wherein the at least 96 percentof the polymers in the mixture each comprise a polyethylene glycolmoiety having from 7 to 50 polyethylene glycol subunits, and wherein theat least 96 percent of the polymers in the mixture each have the samenumber of polyethylene glycol subunits.
 3. The mixture of polymers ofclaim 1, wherein at least 97 percent of the polymers in the mixture havethe same molecular weight, wherein the at least 97 percent of thepolymers in the mixture each comprise a polyethylene glycol moietyhaving from 7 to 50 polyethylene glycol subunits, and wherein the atleast 97 percent of the polymers in the mixture each have the samenumber of polyethylene glycol subunits.
 4. The mixture of polymers ofclaim 1, wherein at least 98 percent of the polymers in the mixture havethe same molecular weight, wherein the at least 98 percent of thepolymers in the mixture each comprise a polyethylene glycol moietyhaving from 7 to 50 polyethylene glycol subunits, and wherein the atleast 98 percent of the polymers in the mixture each have the samenumber of polyethylene glycol subunits.
 5. The mixture of polymers ofclaim 1, wherein at least 99 percent of the polymers in the mixture havethe same molecular weight, wherein the at least 99 percent of thepolymers in the mixture each comprise a polyethylene glycol moietyhaving from 7 to 50 polyethylene glycol subunits, and wherein the atleast 99 percent of the polymers in the mixture each have the samenumber of polyethylene glycol subunits.
 6. The mixture of polymers ofclaim 1, wherein the at least 95 percent of the polymers in the mixtureeach further comprise an ester of a fatty acid moiety covalently coupledto the polyethylene glycol moiety.
 7. The mixture of polymers of claim6, wherein the fatty acid moiety has from 1 to 24 carbon atoms.
 8. Themixture of polymers of claim 6, wherein the fatty acid moiety has from 1to 18 carbon atoms.
 9. The mixture of polymers of claim 6, wherein thefatty acid moiety has from 3 to 20 carbon atoms.
 10. The mixture ofpolymers of claim 6, wherein the fatty acid moiety has from 6 to 18carbon atoms.
 11. The mixture of polymers of claim 6, wherein the esteris a lower alkyl ester.
 12. The mixture of polymers of claim 6, whereinthe ester is an ethyl ester.
 13. The mixture of polymers of claim 6,wherein the at least 95 percent of the polymers in the mixture eachfurther comprise a benzyl moiety covalently coupled to the polyethyleneglycol moiety.
 14. The mixture of polymers of claim 1, wherein the atleast 95 percent of the polymers in the mixture each further comprise afatty acid moiety coupled to the polyethylene glycol moiety.
 15. Themixture of polymers of claim 14, wherein the fatty acid moiety has from1 to 24 carbon atoms.
 16. The mixture of polymers of claim 14, whereinthe fatty acid moiety has from 1 to 18 carbon atoms.
 17. The mixture ofpolymers of claim 14, wherein the fatty acid moiety has from 3 to 20carbon atoms.
 18. The mixture of polymers of claim 14, wherein the fattyacid moiety has from 6 to 18 carbon atoms.
 19. The mixture of polymersof claim 14, wherein the at least 95 percent of the polymers in themixture are activated polymers.
 20. The mixture of polymers of claim 19,wherein the activated polymers each comprise an activating moietyselected from the group consisting of an N-hydroxysuccinimide moiety, anactive phenyl chloroformate moiety, a tresylate moiety, and an acetalmoiety.
 21. The mixture of polymers of claim 1, wherein the at least 95percent of the polymers in the mixture each further comprise an alkylmoiety coupled to the polyethylene glycol moiety.
 22. The mixture ofpolymers of claim 21, wherein the alkyl moiety is a lower alkyl moiety.23. The mixture of polymers of claim 21, wherein the at least 95 percentof the polymers in the mixture each further comprise a lipophilicmoiety.
 24. A substantially monodispersed mixture of polymers, whereinat least 95 percent of the polymers in the mixture each comprise a fattyacid moiety covalently coupled to a polyethylene glycol moiety havingfrom 7 to 50 polyethylene glycol subunits, and wherein the at least 95percent of the polymers in the mixture each have the same number ofpolyethylene glycol subunits.
 25. The mixture of polymers of claim 24,wherein at least 96 percent of the polymers in the mixture have the samemolecular weight, wherein the at least 96 percent of the polymers in themixture each comprise a fatty acid moiety covalently coupled to apolyethylene glycol moiety having from 7 to 50 polyethylene glycolsubunits, and wherein the at least 96 percent of the polymers in themixture each have the same number of polyethylene glycol subunits. 26.The mixture of polymers of claim 24, wherein at least 97 percent of thepolymers in the mixture have the same molecular weight, wherein the atleast 97 percent of the polymers in the mixture each comprise a fattyacid moiety covalently coupled to a polyethylene glycol moiety havingfrom 7 to 50 polyethylene glycol subunits, and wherein the at least 97percent of the polymers in the mixture each have the same number ofpolyethylene glycol subunits.
 27. The mixture of polymers of claim 24,wherein at least 98 percent of the polymers in the mixture have the samemolecular weight, wherein the at least 98 percent of the polymers in themixture each comprise a fatty acid moiety covalently coupled to apolyethylene glycol moiety having from 7 to 50 polyethylene glycolsubunits, and wherein the at least 98 percent of the polymers in themixture each have the same number of polyethylene glycol subunits. 28.The mixture of polymers of claim 24, wherein at least 99 percent of thepolymers in the mixture have the same molecular weight, wherein the atleast 99 percent of the polymers in the mixture each comprise a fattyacid moiety covalently coupled to a polyethylene glycol moiety havingfrom 7 to 50 polyethylene glycol subunits, and wherein the at least 99percent of the polymers in the mixture each have the same number ofpolyethylene glycol subunits.
 29. The mixture of polymers of claim 24,wherein the fatty acid moiety has from 1 to 24 carbon atoms.
 30. Themixture of polymers of claim 24, wherein the fatty acid moiety has from1 to 18 carbon atoms.
 31. The mixture of polymers of claim 24, whereinthe fatty acid moiety has from 3 to 20 carbon atoms.
 32. The mixture ofpolymers of claim 24, wherein the fatty acid moiety has from 6 to 18carbon atoms.
 33. A substantially monodispersed mixture of polymers,wherein at least 95 percent of the polymers in the mixture each consistof a polyethylene glycol moiety having from 7 to 50 polyethylene glycolsubunits and a terminal methyl group at one end of the polyethyleneglycol moiety, and wherein the at least 95 percent of the polymers inthe mixture each have the same number of polyethylene glycol subunits.34. The mixture of polymers of claim 33, wherein at least 96 percent ofthe polymers in the mixture have the same molecular weight, wherein theat least 96 percent of the polymers in the mixture each consist of apolyethylene glycol moiety having from 7 to 50 polyethylene glycolsubunits and a terminal methyl group at one end of the polyethyleneglycol moiety, and wherein the at least 96 percent of the polymers inthe mixture each have the same number of polyethylene glycol subunits.35. The mixture of polymers of claim 33, wherein at least 97 percent ofthe polymers in the mixture have the same molecular weight, wherein theat least 97 percent of the polymers in the mixture each consist of apolyethylene glycol moiety having from 7 to 50 polyethylene glycolsubunits and a terminal methyl group at one end of the polyethyleneglycol moiety, and wherein the at least 97 percent of the polymers inthe mixture each have the same number of polyethylene glycol subunits.36. The mixture of polymers of claim 33, wherein at least 98 percent ofthe polymers in the mixture have the same molecular weight, wherein theat least 98 percent of the polymers in the mixture each consist of apolyethylene glycol moiety having from 7 to 50 polyethylene glycolsubunits and a terminal methyl group at one end of the polyethyleneglycol moiety, and wherein the at least 98 percent of the polymers inthe mixture each have the same number of polyethylene glycol subunits.37. The mixture of polymers of claim 33, wherein at least 99 percent ofthe polymers in the mixture have the same molecular weight, wherein atleast 99 percent of the polymers in the mixture each consist of apolyethylene glycol moiety having from 7 to 50 polyethylene glycolsubunits and a terminal methyl group at one end of the polyethyleneglycol moiety, and wherein the at least 99 percent of the polymers inthe mixture each have the same number of polyethylene glycol subunits.